{60 -(cyclic tert, aminophenyl)-aliphatic acids

ABSTRACT

New Alpha -(cyclic tert. aminophenyl)-aliphatic acids, e.g. those of the formula R1 H or alkyl R2 H, alk(en)yl, cycloalk(en)yl or cycloalk(en)yl-alkyl   Ph a phenylene radical   D R A W I N G

U ite States Patent Carney et al.

[111 3,868,391 [4 1 Feb. 25, 1975 a-( CYCLIC TERT,AMINOPHENYL)-ALIPHATIC ACIDS Inventors: Richard William James Carney,

New Providence; George deStevens, Summit, both of NJ.

Assignec: Ciba-Geigy Corporation, Ardsley,

Filed: Dec. 26, 1972 Appl. No.: 318,158

Related US. Application Data [1.8. (.'l.. 260/326.4l, 260/239 BE,260/293.8l, 260/287 R, 260/295 F, 260/295.5 B, 260/3261, 260/2472 A,260/325 PH, 260/3261 1 R, 260/243 B, 260/295 R, 424/244, 424/263,424/274 Int. Cl C07d 27/14 Field of Search 260/326-41, 260/293-81, 239BE, 295 R [56] References Cited UNITED STATES PATENTS 3,579,535 5/1971Denss 6131. 260/326A1 Primary Examiner-Joseph A. Narcavage Attorney,Agent, or FirmJoseph G. Kolodny; Theodore O. Groeger; John J. MaitnerABSTRACT New a-(cyclic tert. aminophenyl)-aliphatic acids, e.g. those ofthe formula R, H or alkyl cycloalk(en)yl or 1 A A N- Ph- 0- COOH Ph aphcnylcnc radical monoor bicyclic alkenyleneimino with 1-3 doublc bondsand functional derivatives thereof, are antiinflammatory agents.

9 Claims, No Drawings a-(CYCLIC TERT, AMINOPHENYL)-ALIPI-IATIC ACIDSCROSS-REFERENCES TO RELATED APPLICATIONS This is a continuation ofapplication Ser. No. 40,436, filed May 25, 1970, which in turn'is acontinuation-inpart of application Ser. No. 856,154, filed Sept. 8,1969, (all three abandoned) which in turn is a continuation-in-part ofapplication Ser. No. 843,244, filed July 18, 1969, which in turn is acontinuation-in-part of application Ser. No. 808,343, filed Mar. 18,1969, which in turn is a continuation-in-part of application Ser. No.790,863, filed Jan. 13, 1969, which in turn is a continuation-in-part ofapplication Ser. No. 757,136, filed Sept. 3, 1968 (now US. Pat. No.3,657,230), which in turn is a continuation-in-part of application Ser.No. 716,347, filed Mar. 27, 1968 (now abandoned).

SUMMARY OF THE INVENTION The present invention concerns and has for itsobject the provision of new a-(cyclic tert. aminophenyl)- aliphaticacids, more particularly of those corresponding to Formula 1 l A A N-Ph-C- COOH I in which R is hydrogen or lower alkyl, R is hydrogen, loweralkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-alkyl orcycloalkenyl-alkyl, Ph is a phenylene radical and A N- v DESCRIPTION OFTHE PREFERRED EMBODIMENT The lower alkyl radicals R or R represent, forexample, methyl, ethyl, nor i-propyl, -butyl, -pentyl, -hexyl or-heptyl. A lower alkenyl radical R is, for example, vinyl, allyl,methallyl, 3-butenyl or l-pentenyl. The term lower, referred to aboveand hereinafter in connection with organic radicals or compoundsrespectively, defines such with up to 7, preferably up to 4, carbonatoms.

A cycloalkyl or cycloalkenyl radical R is preferably 3 to 7ring-membered and unsubstituted or substituted by up to 4 lower alkyls,such as cyclopropyl, lor Z-methyl-cyclopropyl, 1,2-, 2,2- or2,3-dimethylcyclopropyl, 1,2,2- or 1,2,3-trimethylcyclopropyl or2,2,3,3,-tetramethyl-cyclopropyl, cyclobutyl, 3,3- dimethyl-cyclobutylor 2,2,3-trimethyl-cyclobutyl, cyclopentyl, 2- or 3-methyl-cyclopentyl,2,5- or 3,4-dimethyl-cyclopentyl, cyclohexyl, 2-, 3- or 4-methyI-cyclohexyl, 2,3,2,4- or 3,5-dimethylcyclohexyl or2,4,o-trimethyl-cyclohexyl or cycloheptyl; 2- cyclopropenyl,2,3-dimethyl-Z-cyclopropenyl, l-, 2- or 3-cyclopentenyl or-cyclohexenyl, 2- or 3-methyl-2- cyclopentenyl,3,4-dimethyl-3-cyclopentenyl or 2-, 3- or 4-methyl-l or 2-cyclohexenyl.A cycloalkyl-lower alkyl or cycloalkenyl-lower alkyl radical R is one ofthe above-mentioned lower alkyl groups, preferably such with up to 4carbon atoms, having in any position thereof, preferably at the terminalcarbon atom, one of said cycloalkyl or cycloalkenyl radicals. attached,e.g. cyclopropylmethyl, 2-cyclopentylethyl or 3- cyclopentenylmethyl.

The phenylene radical Ph, carrying the tertiary amino group in the 2-,preferably 3- or especially 4position, is unsubstituted or substitutedin the remaining positions by one or more than one, preferably one ortwo, of the-same or different substituents selected, for example, fromlower alkyl, e.g. methyl, ethyl, nor i-propyl or -butyl, free,etherified or esterified hydroxy or mercapto, such as lower alkoxy orlower alkylmercapto, e.g. methoxy, ethoxy, nor i-propoxy or -butoxy,methylmercapto or ethylmercapto, or halogeno, e.g. fluoro, chloro, bromoor iodo; trifluoromethyl, nitro', amino, preferably dilower alkylaminoor another group or lower alkanoylamino, e.g. dimethylamino, N-methyl-N-ethylamino, diethylamino, di-nor I- propylamino or -butylamino;acetylamino or pivaloylamino, furthermore cyano, carbamoyl, diloweralkylcarbamoyl, carboxy, lower alkylsulfonyl, sulfo, sulfamoyl ordi-lower alkylsulfamoyl, e.g. N,N-dimethylcar'bamoyl or -sulfamoyl,methylor ethylsulfonyl. More particularly, the phenylene radical Phespecially represents, 1,3- or 1,4-phenylene, but also (loweralkyl)-1,3- or 1,4-phenylene, (lower alkoxy)- l,3- or 1,4-phenylene,monoor di-(halogeno)-I,3- or 1,4-phenylene, (trifluoromethyl)-1,3- or1,4- phenylene, (nitro)-l ,3- or 1,4-phenylene, (amino)-1,3- or1,4-phenylene, (di-lower alkylamino)-l,3- or 1,4- phenylene or or1,4-pnenylene.

The cyclic tertiary amino group is preferably a monocyclic 5 to 7ring-membered lower 2- or 3-alkenyleneimino group or a bicyclic loweralkenyleneimino group containing 5 or 6-membered rings, at most onenitrogen atom in each ring and I-3 double bonds in the ring notcontaining the imino nitrogen, e.g. 3-pyrrolino, 3-piperideino,1,4-pent-2- enyleneimino, 2,5- or 1,6-hex-3-enyleneimino, 2,6- or1,7-hept-3-enyleneimino; 4,5,6,7-tetrahydroindolino or -isoindolino,4,7-dihydroindolino or -isoindolino, indolino, isoindolino,1,2,3,4,5,6,7,8-octahydro-, l,2,3,4,5,8-hexahydroorl,2,3,4-tetrahydroquinolino or -isoquinolino; 1-pyrrolo[2,3-b] pyridyl,pyrrolo[3,4-c]pyridyl or 6-pyrrolo[3,4-b]pyridyl. Said cyclic tert.amino groups may be unsubstituted or substituted, for example, in thearomatic portion as shown for Ph above, and in the aliphatic portionespecially by lower alkyl, free, etherified or esterified hydroxy ormercapto, e.g. lower alkoxy, halogeno, lower alkanoyloxy, oxo and/orthiono.

Therapeutically acceptable functional derivatives of the acids ofFormula I are preferably their esters, for example, their lower alkyl,lower alkenyl, 3 to 7 ringmembered cycloalkyl, cycloalkenyl,cycloalkyl-lower alkyl or cycloalkenyl-lower alkyl, aryl or aralkylesters, e.g. the HPh or HPh-lower alkyl esters, free or etherifledhydroxy-lower alkyl, e.g. lower alkoxyor 3 to 7 ring-memberedcycloalkoxy-lower alkyl or tert. aminolower alkyl esters, of which theesterifying moiety has been exemplified above and if it contains heteroatoms, these are separated from each other and the carboxy oxygen by atleast 2, preferably 2 or 3 carbon atoms. A tertiary amino group thereinis, for example, di-lower alkylamino or lower alkyleneimino, e.g.dimethylamino, diethylamino, pyrrolidino or piperidino, or

monothia-lower almonoaza-, monooxaor kyleneimino, such as piperazino,4-lower alkylpiperazino, e.g. 4-(methyl or ethyl)-piperazino, morpholinoor thiamorpholino. Other functional derivatives of the acids of Formula1 are, for example, unsubstituted or substituted amides or thioamides,e.g. monoor di-lower alkylamides, HPh-amides, HPh-lower alkylamides,monocyclic lower alkyleneamides, monoaza-, monooxaor monothialoweralkyleneamides, furthermore the corresponding thioamides, hydroxamicacids, nitriles, ammonium or metal salts. Amino derivatives are theN-oxide, lower alkylor HPh-lower alkyl quaternaries and acid additionsalts.

The compounds of the invention possess valuable pharmacologicalproperties. Besides analgesic and antifungal activity, they exhibitanti-inflammatory effects, as can be demonstrated in in vitro or animaltests, using for the latter advantageously mammals, such as mice, ratsor guinea pigs as test objects. The former tests can be performedaccording to the gradient plate method with fungi selected, for example,from Trichophyton, Microsporum or Epidermophyton, e.g. T.mentagrophytes, T. rubrum or T. sinii; M. canis or M. gypseum; or E.floccosum. The antifungal activity can also be observed in vivo, e.g.according to Molinas, J. lnvestig. Dermatol. 25, 33(1955), where guineapigs are infected on the shaven back with a homogenous agar suspensionof a day old culture of T. mentagrophytes grown on Sabouraud's agar.Treatment with 0.5-2% medicated solutions or ointments is started after24 hours and continued once daily for 10 days. During this time,portions of hair and skin skales are taken from 5 different sites of theinfected area and subcultured on Mycosel agar plates, which areincubated and examined for growth. The anaglesic effects can bedemonstrated, for example, according to the mouse writhing test,described inter alia by Siegmund et al. Proc. Soc. Exp. Biol. & Med. 95729 (1957) at oral doses between about 50 and 200 mg/kg/ day.Antiintlammatory activity can be shown, for example, according to Winteret al., Proc. Soc. Exp. Biol. & Med.

111, 544 (1962). There, the compounds of the invention are applied, inthe form of aqueous solutions or suspensions, which may containcarboxymethylcellulose or polyethylene glycol as solubilizers, bystomach tube to male and female mature rats, in the dosage range betweenabout 0.1 and mg/kg/day, preferably between about 0.5 and 50 mg/kg/day,advantageously between about 1 and 25 mg/kg/day. About 1 hour later 0.06ml of a 1% aqueous saline suspension of carrageenin is injected into therats left hind paw and 3-4 hours subsequently any anti-inflammatoryactivity can be expressed by the difference of the volume and/or weightof the edematous left paw and that of the right paw, as compared withsaid difference estimated from untreated control animals. According tothe adjuvant arthritis test, male rats are sensitized with 0.05 ml ofsaid 1% carrageenin suspension, applied under ether anesthesia to allfour paws. After 24 hours 0.1 ml of a 1% suspension of M. butyricum inmineral oil is injected intradermally into the tail and 7 days later thecompounds of the invention are applied as shown above for a 14 dayperiod. The rats are weighed once weekly and the secondary arthriticlesions scored 3 times a week as to number and severity. The resultsobtained are compared with those of untreated arthritic rats. In view ofthe test results obtained, the compounds of the invention are usefulanalgesic, antifungal and especially antiinflammatory agents in thetreatment or management of arthritic and dermatopathologic conditions.They are also useful intermediates in the preparation of other valuableproducts, preferably of pharmacologicaly active compounds.

Preferred compounds of the invention are those of Formula 1 in which:

a. R, is hydrogen or lower alkyl, R is hydrogen, lower alkyl or loweralkenyl, Ph is unsubstituted phenylene or phenylene substituted by oneor two members selected from the group consisting of lower alkyl,hydroxy, mercapto, lower alkoxy, lower alkylmercapto, halogeno,trifluoromethyl, nitro, amino, di-lower alkylamino,

A it...

lower alkanoylamino, cyano, carbamoyl, di-lower alkyl-carbamoyl,carboxy, lower alkylsulfonyl, sulfo, sulfamoyl or di-loweralkyl-sulfamoyl, and the group is monocyclic 5 to 7 ring-membered lower2- or 3- alkenyleneimino or bicyclic alkenyleneimino containing 5 or6-membered rings, at most one nitrogen atom in each ring and 1-3 doublebonds in the ring not containing the imino nitrogen, which imino groupsare unsubstituted or substituted by one or two oxo groups at the carbonatoms adjacent to the imino nitrogen;

b. R Ph and have the meaning given under item a) and R is 3 to 7ring-membered cycloalkyl, cycloalkenyl, cycloalkyllower alkyl orcycloalkenyl-lower alkyl, or a lower alkyl ester, lower alkenyl ester, 3to 7 ring-membered cycloalkyl ester, cycloalkenyl ester,cycloalkyl-lower alkyl ester, cycloalkenyl-lower alkyl ester, HPh-ester,HPhlower alkyl ester, hydroxy-lower alkyl ester, lower alkoxy-loweralkyl ester, di-lower alkylamino-lower alkyl ester, loweralkyleneim-ino-lower alkyl ester, monoaza-, -oxaor -thia-loweralkyleneimino-lower alkyl ester or A A N- lower alkyl ester in whichesters 2 hetero atoms are separated from each other by at least 2 carbonatoms, the amide, thioamide, a monoor di-lower alkylamide, monoordi-lower alkyl-thioamide, lower alkyleneamide, lower alkylenethioamide,l-lPh-amide, HPh-thioamide, HPhlower alkylamide, HPh-loweralkylthioamide, morpholide, thiamorpholide or hydroxamic acid, theN-oxide, a lower alkyl quaternary, HPh-lower alkyl quaternary or atherapeutically useful salt of the compounds listed under items (a) or(b).

Particularly'useful are the compounds of Formula I, in which:

c. R, is hydrogen, R is hydrogen or lower alkyl, Ph is l,3- orl,4-phenylene, (lower alkyl)-l,3- or l,4- phenylene, (lower alkoxy)-l,3-or l,4-phenylene, monoor tli-(halogeno)-l ,3- or l,4-phenylene,(trifluoromethyl)-l,3- or l,4-phenylene, (nitro)-1,3- or l,4-phenylene,(amino-1,3- or l,4-phenylene, (dilower alkylamino-l,3- or l,4-phenyleneor or l,4-phenylene, the group is monocyclic 5 to 7 ring-membered lower2- or 3- alkenyleneimino or bicyclic alkenyleneimino containing only onenitrogen atom, 5 or 6-membered rings and 1-3 double bonds in theisocyclic ring, or said alkenyleneimino radicals containing one or twooxo groups attached to the carbon atoms adjacent to the nitrogen atom;

(1. R Ph and Am i in which:

e. R;, is hydrogen or alkyl with up to 4 carbon atoms, R, is hydrogen,alkyl or alkoxy with up to 4 carbon atoms, halogeno, trifluoromethyl,nitro or amino, and Am is 3-pyrrolino, 3-piperideino, l,6-hex-3-enyleneimino, indolino, isoindolino or 1,2,33,4- tetrahydroquinolino or-isoquinolino, or said radicals containing one or two oxo groupsattached to the carbon atoms adjacent to the nitrogen atom;

f. R, and Am have the meaning given under item (e) and R is 3 0r 4ring-membered lower cycloalkyl or cycloalkylmethyl, or the methyl,ethyl, nor i-propyl or -butyl ester, the N-oxide, sodium or potassiumsalt or a therapeutically useful acid addition salt of the compoundslisted under items (e) and (f).

Especially valuable are compounds of the Formula II, in which:

g. R is hydrogen, methyl, ethyl, nor i-propyl, R is hydrogen, fluoro,chloro or trifluoromethyl and Am is 3-pyrrolino, 3-piperideino,2-oxo-3-pyrrolino, maleinimino, isoindolino, l-oxo-isoindolino,phthalimino or homophthalimino;

h. R, and Am have the meaning given under item (g) and R is cyclopropylor cyclopropylmethyl, the methyl or ethyl ester, the N-oxide, sodium orpotassium salt or a therapeutically useful acid addition salt of thecompounds listed under items (g) and (h).

The most preferred embodiments of the present invention are thea-(3-chloro-4-pyrrolinophenyl)- propionic acid, the methyl or ethylester, the N-oxide,

sodium or potassium salt or a therapeutically useful acid addition saltthereof, which exhibit in the abovedescribed test systems at dosesbetween about 1 and 25 mg/kg/day a high order of anti-inflammatoryactivity.

The compounds of this invention are prepared according to methods knownper se. For example, they are obtained by:

a. converting in a compound of the Formula Ill Ha -x (511.31

in which X, is a substituent capable of being converted into the free orfunctionally converted moiety, X, into said acid group or b. convertingin a compound of Formula IV or a functional derivative thereof, in whichX is a substituent capable of being converted into According to process(a), the compounds of the invention are prepared either by a)introduction of the whole free or functionally converted acid moiety orany part thereof (preferably the carboxylic function), into compounds ofFormula III, or by B) liberation of said acid moiety from a suitablegroup containing already the required number of carbon atoms, i.e. theliberation of a potential carboxy or alkylidene moiety.

Accordingly, the simplest substituent X, is a hydrogen atom, a metallicgroup or a reactively esterified hydroxy group. The former is, forexample, an alkali metal, eg. a lithium atom, or a substituted alkalineearth metal, zinc or cadmium atom, such as halomagnesium or lower alkylzinc or cadmium, e.g. chloro-, bromoor iodomagnesium, methyl or ethylzinc or cadmium. A reactively esterified hydroxy group is preferablysuch derived from a strong mineral or sulfonic acid, such as ahydrohalic, sulfuric, lower alkane or benzene sulfonic acid, e.g.hydrochloric, hydrobromic, methane-, ethane-, benzeneor ptoluenesulfonicacid. The corresponding starting material of Formula III is reacted withthe acid having the formula R1\ coon or a suitable derivative, e.g. acorresponding salt, ester, amide or nitrile thereof, in which formulaeone of X, and Y, is the above-described metallic group and the othersaid reactively esterified hydroxy group, or X, is hydrogen and Y, is afree or reactively esterified hydroxy group. Such reaction is performedaccording to the classical Grignard or Friedel-Crafts syntheses, inwhich a new carbon-carbon bond is formed from separate reactants. Thelatter synthesis is performed in the presence of a Lewis acid, such asan aluminum, boron, antimony V, ferric or zinc salt, e.g. the chloridesthereof, or hydrofluoric, sulfuric or preferably polyphosphoric acid,which latter agent is advantageously used with the above glycolic acidsor their derivatives, i.e. those in which Y, is hydroxy. In case X, is ahydrogen atom and Ph contains a free or functionally convertedy-carboxy-Z-alkenyloxy group in the ortho or para position thereto, suchallyl ether starting material, e.g. that of the formula A N- Ph-O- CHCH=CH- C003 can be rearranged according to the Claisen (Cope)rearrangement procedure, for example, by heating it up to about 300 orless, to yield compounds of Formula I in which R, is lower alkenyl andPh contains a hydroxy group ortho or para to the acid moiety, orfunctional acid derivatives, e.g. esters or lactones, thereof. Thesubstituent X, in Formula III is also the group in which Y, is ametallic group, e.g. such mentioned above, an ammonium group, such astri-lower alkylam monium or di-lower alkyl-aralkylammonium, e.gtrimethylammonium or dimethylbenzylammonium, or a free or reactivelyconverted, such as esterified, etherified or salified, hydroxy group,e.g. such esterified as mentioned above, or etherified with a loweralkanol or aralkanol, or salified with an alkali or alkaline earthmetal, e.g. sodium, potassium or calcium. Such metal compound, ester,ether or alcoholate of Formula III is reacted with a reactive derivativeof carbonic or formic acid, whereby both reactants at most contain onemetal atom. The metal or Grignard compound can be reacted with anysuitable, metal free carbonic or formic acid derivative, advantageouslycarbon dioxide or disulfide, but also a corresponding carbonate orhaloformate, e.g. diethyl carbonate or thiocarbonate; ethyl or propylorthocarbonate; ethyl, tert, 'butyl, allyl, 2-methoxyethyl,3-chloropropyl, phenyl or benzyl chloroformate; cyanogen or carbamoylhalides, e.g. cyanogen bromide or diethylcarbamoyl chloride. Thestarting material, in which Y, is an ammonium or free or reactivelyconverted hydroxy group, is advantageously reacted with a metal cyanide,e.g. sodium or potassium cyanide, and that in which Y, is free,esterified or salified hydroxy, or the dehydrated unsaturated derivativethereof (wherein X, is a corresponding l-alkenyl group), can alsobe'reacted with carbon monoxide. The latter maybe applied under neutral,basic or acidic conditions respectively, e.g. in the presence ofsulfuric acid, under high pressure and/or temperature, e.g. up to 400 atand 300, advantageously in the presence of heavy metal catalysts, e.g.nickel or cobalt salts or carbonyl derivatives thereof. The carbonmonoxide may also be generated from appropriate sources, such as formicacid and high boiling mineral acids, e.g. sulfuric or phosphoric acid.

Another substituent X, is the group wherein Y, is a substituentconvertible into a free or functionally converted carboxy group. Theconversion of Y into the latter group can be performed either byoxidation or rearrangement. In the former case Y, is, for example,methyl, hydroxymethyl, borylmethyl, hydroxyiminomethyl, formyl, lowerl-alkenyl or 1- alkynyl, lower l,2 dihydroxyalkyl or acyl, such as loweralkanoyl, alkenoyl, free or esterified carboxycarbonyl. In thecorresponding starting material of Formula III, containing saidpotential carboxy function, Y, is transformed into free or functionallyconverted carboxy according to standard oxidation methods, for example,with the use of air or pure oxygen, preferably in the presence ofcatalysts, such as silver, manganese, iron or cobalt catalysts, or withoxidation agents, e.g. hydrogen peroxide or nitric oxides, oxidizingacids or their salts, such as hypohalous, periodic, nitric orpercarboxylic acids or suitable salts thereof, e.g. sodium hypochloriteor periodiate, peracetic, perbenzoic or monoperphthalic acid, heavymetal salts or oxides, such as alkali meta @hrqmat .Qr ps a ana ssa.QlEP'EE was salts, e.g halides or sulfates thereof, or silver,mercuric, vanadium V, chromium V] or manganese IV oxide, in acidic oralkaline media respectively. In said oxidations, for which startingmaterials are chosen, in which A an... M

is less sensitive to oxidation than Y e.g. bicyclic alkenyleneimino,usually the free carboxylic acids of Formula I, or salts thereof, areobtained. However, by subjecting, for example, a hydroxyiminomethylcompound (oxime) to Beckmann rearrangement, e.g. treatment with sulfuricacid, p-toluenesulfonyl chloride or phosphorus pentachloride, or tooxidation, eg with hydrogen peroxide or any of said percarboxylic acids,or reacting the corresponding formyl or acyl compound (aldehyde orketone) with hydrazoic acid according to the Schmidt reaction, e.g. inthe presence of sulfuric acid, or the aldehyde with a sulfonyl ornitro-hydroxamate, a nitrile, amide or hydroxamic acid will be formedrespectively. A starting material in which Y is free or esterifiedcarboxycarbonyl, e.g. lower carbalkoxycarbonyl, can be converted intothe acid of Formula I either by oxidation, e.g. with hydrogen peroxidein acidic media, such as mineral acids, or by decarbonylation, whichpreferably is carried out by pyrolysis, advantageously in the presenceof copper or glass powder.

Finally, the substituent X, in Formula III may be such a moiety, whichprimarily is capable of liberating the required alkylidene group I R 1--R Sqsbom istx is, rn awa st tts 9 QLQJEQFLQEH! converted group .R 1,2\.COOH .10- COOH,

wherein each of Y, or Y are convertible into R; and/or R respectively,for example, by reduction, decarboxylation, deacylation ordesulfurization. For example, Y,, is a free or reactively esterified oretherified hydroxy or mercapto group as mentioned above, eg hydroxy,mercapto, chloro, bromo, iodo, benzyloxy or benzylmercapto and Y a loweralkylidene, cycloalkylidene, cycloalkyl-alkylidene, 0x0 or thiono group.The corresponding starting material, or the quaternary 0- orpquinonmethides thereof, obtainable by splitting off Y H from saidcompounds of Formula III, in which at least one of R and R is hydrogen,e.g. with the use of strong mineral acids or alkalis, can be reducedeither with catalytically activated or nascent hydrogen, such ashydrogen in the presence of nickel, palladium or platinum catalysts, orwith hydrogen generated by electrolysis or the action of metals onacids, alkalis or alcohols, such as zinc, amalgamated zinc, iron or tinon aqueous mineral or carboxylic acids, e.g. hydrochloric or aceticacid. zinc or aluminum-nickel alloys on aqueous alkali metal hydroxides,or sodium, potassium or their amalgams on lower alkanols. Also reducingandfor desulfurizing agents may be applied, depending on the startingmaterial chosen. In case Y, is hydroxy, the

reducing agent may be an aqueous suspension of phosphorus and iodine,hydriodic acid, stannous chloride or sodium sulfite or dithionite, or incase Y, is esterified hydroxy, e.g'. halogeno, an aliphatic orcycloaliphatic metal compound, e.g. a corresponding R or R lithium orGrignard compound may be used as reducing agent. The latter metalcompounds may also be applied in the reduction of said quinonmethides.In case Y is oxo, the Clemmensen, Wolff-Kishner or I-Iuang-Minlonprocedures may be applied, wherein nascent hydrogen or hydrazine areused, the latter advantageously in the presence of strong alkalis, e.g.high boiling aqueous or glycolic sodium or potassium hydroxidesolutions. In the reduction of mercapto, free or ketalized thionocompounds, desulfurization agents are advantageously applied, such asmercury or copper oxide or Raney nickel. In case Y; represents carboxy,the corresponding malonic acid derivative is decarboxylated bypyrolysis, advantageously in acidic media, or Y, stands for another acylradical, such as lower alkanoyl or aralkanoyl, e.g. acetyl or benzoyl,the B-keto acid is subjected to acid splitting by the action of strongalkalis, e.g. those mentioned above.

Another substituent X also providing said alkylidene group, is anunsubstituted or substituted acetyl group, eg CO-(CN )-R or CO-(CR ,R)-halogen. The corresponding unsubstituted acetyl starting material isconverted into the compounds of the invention according to theWillgerodt-Kindler reaction, e.g by the action of sulfur in the presenceof ammonia, primary or secondary amines and advantageously of sulfonicacids, e.g. p-toluenesulfonic acid, and said substituted acetylcompounds according to the Wolff (Arndt- Eistert) reaction, e.g. byhydrolysis, alcoholysis, ammonolysis or aminolysis of correspondinga-diazo-ketones, advantageously while irradiated or heated in thepresence of copper or silver catalysts, or according to the Favorskii(Wallach) reaction respectively, e.g. by the action of strong alkalis orsoluble silver salts, such as silver nitrate, on correspondinga-haloketones.

According to process b), the cyclic tertiary amino group bly an alkalimetal or halogen atom respectively. The

corresponding starting material of Formula IV is reacted with thecompound A N Y' in which one of X and Y, is hydrogen or said metallicgroup, e.g. lithium or sodium, and the other said free or reactivelyesterified hydroxy group, e.g. fluorine or chlorine. In case X ishydrogen and Y halogen, the reaction is carried out analogous to theFriedel-Crafts sytheses mentioned above, i.e in the presence of Lewisacids or, in case Y, is hydroxy, in the presence of alkalis, e.g.potassium hydroxide. In case X is hydroxy or lower alkanoyloxy, thereaction is advantageously carried out in the presence of a dehydrationor dehydrogenation catalyst, such as a mineral acid or a salt thereof,e.g. hydrochloric acid, ammonium sulfite or sodium bisulfite, activatedaluminum oxide, Raney nickel or palladium-charcoal.

The conversion of any primary, secondary, acyclic or saturated cyclictertiary amino group X into can simply be performed by transaminationwith the amine A N-H.

The latter is advantageously used in excess and in the presence orabsence of catalysts, e.g. the abovementioned dehydration ordehydrogenation catalysts, and elevated temperature and/or pressure. Astarting material of Formula IV, in which X is primary amino, can alsobe reacted with the glycol, glycolic acid or dicarboxylic acid HO-A-OH,or advantageously a reactive functional derivative thereof, such as anester, cyclic ether or the dehydrated, unsaturated (olefinic) derivativeof said glycol or glycolic acid and/or a halide, anhydride or lactone ofthe acid, e.g. such mentioned above. These condensations areadvantageously carried out in the presence of water or acid bindingagents, such as alkali metals, their alcoholates or carbonates, and theaddition of the unsaturated compounds to the amino group preferably inthe presence of catalysts, e.g. copper, cobalt or molybdenum catalysts,and/or acids or bases. A saturated cyclic tert. amino group X can beconverted into the unsaturated group, for example, by dehydration,dehydrosulfidation or desamination of a monoor bicyclic (hydroxy,mercapto, amino, ammonium, hydrazino or hydrazono)- alkyleneimino group,or reactive derivatives thereof, such as a reactive ether or ester ofthe hydroxy or mercapto compounds, or an acyl derivative of the nitrogenbases, e.g a tert. butyl ether or a tosylate, brosylate or xanthaterespectively. Dehydration is preferably carried out with the use ofconcentrated mineral or sulfonic acids, Lewis acids or carboxylic acidanhydrides, e.g. hydrobromic, sulfuric, phosphoric or p-toluenesulfonicacid or acetic anhydride. Dehydrosulfidation may be carried out with theuse of heavy metal oxides,

I e.g. mercury or lead oxide and desamination by thermal decompositionof ammonium salts. Preferably reactive esters of the hydroxy compoundsor acyl derivatives of the hydrazones are pyrolyzed, advantageouslyunder reduced pressure.

The compounds of the invention so obtained can be converted into eachother according to methods known per se. For example, resulting freeacids may be esteritied with the corresponding alcohols in the presenceof a strong acid, e.g. hydrochloric, sulfuric, benzene or ptoluenesulfonic acid, or with diazo compounds, or converted into their halidesby treatment with thionyl halides or phosphorus halides or oxyhalides.Resulting esters may be hydrolyzed or transesterified in the presence ofacidic or alkaline agents, e.g mineral or complex heavy metal acids oralkali metal carbonates or alcoholates, or treated with ammonia orcorresponding amines. Resulting acid halides may be treated withalcohols, ammonia or amines in order to obtain the corresponding estersor amides respectively. Resulting amides or thioamides (Willgerodt) canbe hydrolyzed under acidic or alkaline conditions, e.g with the use ofaqueous mineral and/or carboxylic acids or alkali metal hydroxides, alsoalcohlyzed, transaminated or desulfurized, e.g. with the use of mercuricoxide or alkyl halides followed by hydrolysis, or oxo compoundssulfurized, e.g. with phosphorus pentasulfide. Resulting compounds whichdo not contain an oxo group in the bicyclic moiety can be oxidizedtherein already with oxygen or other mild oxidation agents, e.g. thosementioned above, to introduce an oxo group into the the A-radicalthereof, preferably into one or both of the positions adjacent to theimino nitrogen, thus converting the cyclic tertiary amines into lactamesor imides respectively. Resulting nitriles likewise can be hydrolyzed oralcholyzed, e.g with the use of concentrated aqueous or alcoholic acidsor alkalis or also with alkaline hydrogen peroxide. A resulting ester,salt or nitrile, containing in (X-pOSlllOn at least one hydrogen atom,can be metallized therein, e.g. with the use of alkali metals or theirderivatives, such as phenyl lithium, triphenylmethylsodium or sodiumhydride, amides or alcoholates, and thereupon reacted with reactiveesters of R,-OH and/or R -OH. Resulting compounds may also behalogenated in the Ph-moiety, e.g. with the use of halogens, which areadvantageously applied in the presence of Lewis acids, e.g. ferric,aluminum, antimony Ill or tin IV halides, or with the use ofhalogenation agents, e.g. hydrochloric acid and hydrogen peroxide orsodium chlorate, nitrosyl chloride or bromide, bromosuccinorphthalimide. Furthermore, nitration may be applied to final products,advantageously with the use of nitric acid or nitrates under acidicconditions, e.g in the presence of sulfuric or trifluoroacetic acidrespectively. Resulting nitro compounds may be reduced, for example,with catalytically activated or nascent hydrogen and, if desired, theprimary amino compounds obtained, either treated with reactive esters orcorresponding alcohols or glycols, or with reactive functional acidderivatives, in order to obtain secondary, tertiary, quaternary oracylated amino compounds respectively. Said prim. amines can also betreated with nitrous acid, to yield diazonium salts, which can beconverted according to the Sandmeyer reaction into the correspondinghydroxy, halogeno, cyano, alkoxy or alkylmercapto compounds, e.g. byhydrolyzing the diazonium salt at elevated temperatures, or reacting itwith cuprous halides or cyanide, or with a lower alkanol oralkylmercaptan respectively, preferably under neutral or slightly acidicor alkaline conditions. In resulting phenolic products, the hydroxy ormercapto group can be etherified, e.g by reacting the correspondingalkali metal phenolates with lower alkyl halides or sulfonates, orresulting phenol ethers are hydrolyzed, e.g. with the use of strongacids or acidic salts, e.g. hydrobromic and acetic acid or pyridinehydrochloride, and aliphatic hydroxy compounds can be dehydrated asshown above. In the above reductions, care should be taken or startingmaterials an final products properly selected, in order to retainunsaturation in A A N- A resulting acid can be converted into its saltsaccording to conventional methods, for example, by reacting it with anabout stoichiometric amount of a suitable salt-forming reagent, such asammonia, an amine or an alkali or alkaline earth metalhydroxide,carbonate or hydrogen carbonate. A salt of this type can be reconvertedinto the free acid by treatment with an acid, e.g. hydrochloric,sulfuric or acetic acid, until-the proper pH has been reached. Aresulting basic compound can be converted into a corresponding acidaddition salt, for example by reacting it with an inorganic or organicacid, such as a therapeutically useful acid, or with a correspondinganion exchange'preparation, and isolating the desired salt. An acidaddition salt may be converted into the free compound by treatment witha base, e.g. a metal hydroxide, ammonia or a hydroxyl ion exchangepreparation. Therapeutically useful acids, are, for example, inorganicacids, e.g. hydrochloric, hydrobromic. sulfuric, phosphoric, nitric orperchloric acid, or organic acids. e.g. carboxylic or sulfonic acids,such as formic, acetic, propionic, succinic, glycollic, lactic. malic,tartaric, citric, ascorbic, maleic, hydroxymaleic, pyroracemic,phenylacetic, benzoic, 4- aminobenzoic, anthranilic, 4-hydroxybenzoic,salicylic, aminosalicylic, embonic, nicotinic, methanesulfonic,ethanesulfonic, hydroxy-ethanesulfonic, ethylenesulfonic,benzenesulfonic, halogenbenzenesulfonic, toluenesulfonic,naphthalenesulfonic and sulfanilic acid; methionine tryptophan, lysineand arginine.

These or other salts, for example, the picrates, can also be used forpurification of the bases obtained; the bases are converted into salts,the salts are separated and the bases are liberated from the salts. Inview of the close relationship between the free compounds and thecompounds in the form of their salts, whenever a compound is referred toin this context, a corresponding salt is also intended, provided such ispossible or appropriate under the circumstances.

Resulting mixtures of isomers can be separated into the single isomersby methods in themselves known, e.g. by fractional distillation,crystallization and/or chromatography. Racemic products can likewise beresolved into the optical antipodes, for example by separation ofdiastereomeric salts thereof, e.g. by the fractional crystallization ofdor l-tartrates or d-a-(lnaphthyl)-ethylamine or l-cinchonidine salts.

The above reactions are carried out according to standard methods, inthe presence or absence of diluents, preferably such as are inert to thereagents and are solvents thereof, of catalysts, condensing orneutralizing agents and/or inert atmospheres, at low temperatures, roomtemperature or elevated temperatures, at atmospheric or superatmosphericpressure.

The invention also comprises any modification of the above process,wherein a compound resulting as airin- 14 termediate at an y stagethereof, is used as startingrii' terial and the remaining steps arecarried out, or the process is discontinued at any stage thereof, or inwhich the starting mateial is formed under the reaction conditions or isused in the form of its salts or reactive derivatives. For example, inmost of the above-described oxidation methods, wherein Y is convertedinto a free or functionally converted carboxy group, the correspondingaldehydes (Y is formyl) are formed intermediarily. According to thehaloform reaction (Y is acetyl) intermediarily formed trihaloketones arehydrolyzed under the applied alkaline conditions, to yield thecorresponding salts or esters of the acids of Formula I. Also, thequaternary 0- or p-quinomethides may be formed intermediarily from thecorresponding starting material in which Y, is free or reactivelyesterified hydroxy, e.g. under strongly acidic or alkaline conditions,or during the reduction of compounds in which Y is oxo or thiono. The adiazoketones are usually formed, according to Arndt-Eistert, from thecorresponding benzoic acidhalides and aliphatic or cycloaliphatic (Rdiazo compounds, whereupon the above-described Wolff rearrangement isperformed; Moreover, in the formation of the cyclic tert. amino groupseveral intermediates are formed from' the various starting materialsmentioned above. For example, in the reaction of compounds of FormulaIV, in which X is primary amino, with those ofthe formula HO-A-OH or itsreactive functional derivatives, usually secondary amines or amidesareformed, wherein X is -NH-A- OH,or reactive amino derivatives of suchintermediates. In the process of the invention, those starting materialsare advantageously selected, which yield the above-described preferredembodiments of the invention, especially those corresponding to Formulall.

The starting material used is known or, if new, may be preparedaccording to the methods described for known analogs thereof. Forexample, compounds of Formula "I can be prepared analogous to theprocess mentioned under item (b), i.e. by introduction or constructionof the cyclic amino group ln case X, is a reactively esterified hydroxygroup, it may also be introduced either by halogenation, or nitrationfollowed by reduction, diazotization and Sandmeyer reaction. Theresulting starting material may be subsequently converted into themetallic compounds, e.g. by reaction with alkali or alkaline earthmetals, such as lithium or magnesium, or with dialkyl zinc or cadmium.The allyl ethers for the Claisen rearrangement can be prepared analogousto those described in J. Chem. Soc. 4210 (1963).

The starting material in which Y is a metallic group may be prepared asshown above, i.e. by reacting reactive esters of the correspondingbenzylalcohols with alkali or alkaline earth metals or dialkyl zinc orcadmium. Otherwise, according to Friedel-Crafts, easily ob ainab e l earQYQlQFlk'slFlPr qralk phsnqnss W W Uh Ph- C- R may be reduced eitherwith lithium aluminum hydride or with R -magnesium halides, or

KJ- Ph- Grigna rd compounds reacted with RQ-CO-R to yield thecorresponding benzyl alcohols, whose hydroxy group may be reactivelyesterified or salified according to well-known methods, e.g. by reactionwith phosphorus, thionyl or sulfonyl halides, alkali or alkaline earthmetals respectively and the resulting esters or salts may be convertedinto ethers either by reaction with alcoholates or reactive estersrespectively. The compounds in which Y is an ammonium group, can beobtained from the former reactive esters and secondary amines and theresulting tertiary amines are quaternized in the usual manner, e.g. byreaction with lower alkyl or aralkyl halides.

The starting material containing Y can be obtained from the formercompounds in which Y is a metallic group, by reacting them with a methylhalide, formaldehyde, aformyl halide, lower alkanal, alkenal orhydroxyalkanal or a lower alkanoyl, alkenoyl or oxalyl haliderespectively and, if deisred, dehydrating resulting alcohols by theaction of acidic agents, e.g. sulfuric acid or phosphorus pentoxide, toyield unsaturated derivatives thereof. The latter, e.g. methylidenecompounds, may be reacted with boranes in order to obtain borylmethylcompounds and aldehydes with hydroxylamine, to yield thehydroxyiminomethyl compounds (oximes). The aldehydes, i.e. compounds inwhich Y is formyl, can also be obtained from said ketones A N-Ph- CO-Rby reaction with dimethylsulfoniummethylide ordimethyloxysulfoniummethylide (generated from the correspondingtrimethylsulfonium salts) and rearranging the resulting ethyleneoxidesto the corresponding aldehydes by the action of Lewis acids, e.g.p-toluene sulfonic acid or boron trifluoride, or according to theDarzens condensation by reacting the above ketones with a-halo-alkanoicor alkenoic acid esters in the presence of alcoholates, e.g. potassiumtert. butoxide, saponifying the glycidic esters formed and rearrangingand decarboxylating them, advantageously in acidic media, e.g. sulfuricacid.

The starting material containing Y,,, which represents free, esterifiedor etherified hydroxy or mercapto, can be prepared according to thecyanohydrin or analog syntheses, e.g. by reaction of compounds A lN-Ph-CO-R or their thiono analogs, with aqueous potassium cyanide underacidic conditions and, if desired, converting resulting nitriles intoother acid derivatives and/or alcohols into corresponding mercaptocompounds or reactive esters or ethers thereof, or dehydrating them tounsaturated derivatives. The compounds in which Y is oxo or thiono canbe obtained according to Friedel- Crafts with the use of suitable AN-Ph-H compounds and oxalyl halides. The resulting phenylglyoxylic acidesters may then be reduced with R Grignard compounds, if desired,followed by dehydration. Said compounds may also be prepared accordingto the Ando synthesis by reaction with mesoxalates in Thepharmacologically active compounds of the invention are useful in themanufacture of pharmaceutical compositions containing an effectiveamount thereof in conjunction or admixture with excipients suitable foreither enteral, parenteral or topical application. Preferred are tabletsand gelatin capsules comprising the active ingredient together with(aldiluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol,cellulose and/or glycine, (b) lubricants, e.g. silica, talcum, stearicacid, its magnesium or calcium salt and/or polyethyleneglycol, fortablets also (c) binders. e.g. magnesium aluminum silicate, starchpaste, gelatin. tragacanth, methylcellulose, sodiumcarboxymethylcellulose and/or polyvinylpyrrolidone, if desired. (d)disintegrants, e.g. starches. agar, alginic acid or its sodium salt,enzymes of the binders or effervescent mixtures and/or (e) adsorbents,colorants, flavors and sweeteners. lnjectable compositions arepreferably aqueous isotonic solutions or suspensions, and suppositoriesor ointments are advantageously fatty emulsions or suspensions. They maybe sterilized and/or contain adjuvants, such as preserving, stabilizing,wetting or emulsifying agents, solution promoters, salts for regulatingthe osmotic pressure and/or buffers. Said pharmaceutical compositionsmay also contain other therapeutically valuable substances. They areprepared according to conventional mixing, granulating or coatingmethods respectively and contain about 0.1 to preferably about 1 to 50%of the active ingredient.

The following examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. Temperatures are givenin degrees Centigrade, and all parts wherever given are parts by weight.

EXAMPLE 1 The mixture of 10.8 g ethyl 4-amino-phenylacetatehydrochloride, 32.4 g 1,4-dibromo-2-butene, 84 g sodium bicarbonate and500 ml dimethylformamide is refluxed for 6 hours while stirring,filtered hot and the filtrate evaporated in vacuo. The residue is takenup in ml 25% aqueous sodium hydroxide, the mixture refluxed for 1 hour,cooled and washed with diethyl ether. it is adjusted to pH withhydrochloric acid, extracted with diethyl ether, the extract dried,filtered and evaporated, to yield the 4-pyrrolino-phenylacetic acid ofthe formula melting at l 62-165 EXAMPLE 2 To the stirred mixture of 5,5g ethyl 4-pyrrolinophenylacetate, lOO ml dimethylformamide and 100 mltoluene, 1.25 g 54% sodium hydride in mineral oil are added portionwiseand stirring is continued for 1 /2 at room temperature. Hereupon thesolution of 6.8 g methyl iodide in 25 ml toluene is added dropwiseduring minutes and the mixture is stirred overnight at room temperature.It is evaporated in vacuo, the residue taken up in 75 ml 10% aqueouspotassium hydroxide and the mixture heated at the steam cone for 2hours. It is cooled, adjusted to pH 5 with hydrochloric acid, extractedwith diethyl ether; the extract is dried, concentrated, the concentratediluted with petroleum ether, and the precipitate formed filtered off,to yield the oz-(4-pyrrolinophenyl)-propionic acid of the form u la CH-coon melting at l97l99 after recrystallization from ethanol.

By replacing in this example the methyl iodide by an equivalent amountof ethyl iodide, allyl bromide, 3- cyclopentenyl bromide orcyclopropylmethyl bromide, the ethyl a-(4-pyrrolinophenyl)-(butyrate, 4-pentenoate, a-3-cyclopentenylacetate or Cit-CYCiO- propylmethylacetate)are obtained.

The 3- or 4-amino-phenylacetic or -a-phenylpropionic acid ethyl esters,sodium salts or the 2,3- or 4- chlorinated derivatives thereof, can alsobe reacted with 1,4-dibromo-2-butene, 1,5-dibromo-2-pentene or1,6-dibromo-3-hexene in the presence of sodium bicarbonate, as shown inExample 1, to yield inter alia the ethyl 3- or 4-(pyrrolino,2-pentenyleneimino or 3- hexenyleneimino)-phe nylacetate or-a-phenylpropionate or the corresponding 4- or 3-chloro derivativesthereof.

The 3- or 4-amino-phenylacetic of -a-phenylproionic acid or the 2-, 3-or 4-chlorinated derivatives thereof, can also be reacted with aliphaticdicarboxylic acid dichlorides or anhydrides, e.g. maleic or glutaconicacid anhydride, to yield inter alia the c'x-[4-(2,5-dioxo-pyrrolino)-phenyl]-propionic acid,4-(2,6-dioxohex-3-enyleneimino)-phenylacetic acid or oz-[3-chloro-(2,6-dioxo-hex-3-enyleneimino)-phenyl]-propionic acid.

Moreover, the 4-fluoro-phenyl-acetonitrile can be reacted with4-oxo-piperidine, to yield the 4-(4-oxopiperidino)-phenyl-acetonitrile,which can be hydrolyzed to the free acid and the acid esterified, or theethyl oz-(3-chloro-4-aminophenyl)-propionate reacted with4-oxo-2,5-heptadienedioic acid diethyl ester, saponifying anddecarboxylating the reaction product, to yield thea-[3-chloro-4-(4-oxo-piperidino)-phenyl]- propionic acid. Incorresponding esters, the carbonyl group can be reduced with oneequivalent of Grignard compounds, e.g. methyl-, ethyl-, n-propyl-,phenylor 4-chlorophenyl-magnesium bromide, to yield, inter alia, theethyl 4-[4-hydroxy-4-(methyl, ethyl, n-propyl, phenyl or4-chlorophenyl)-piperidino]-phenyl acetate ora-[3-chloro-4-(4-hydroxy-4-methylpiperidino)- phenyl]-propionate. Saidesters or the corresponding acids can be dehydrated with sulfuric orphosphoric acid, to yield, for example, the 4-(3-n-propyl-pent-2-enyleneimino)-phenylacetic acid or the a-[3-chloro-4-(3-methyl-pent-2-enyleneimino)-phenyl]-propionic acid.

EXAMPLE 3 To the ute ifii lethL fiz -a zfi z phenyl)-propionatepropionate hydrochloride, 142 g sodium carbonate and 600 ml dimethylformamide, 107 g l,4-dibromo-2butene are added dropwise while stirringand the whole is refluxed for 5 hours and allowed to stand overnight atroom temperature. The mixture is filtered, the filtrate evaporated invacuo, the

residue is triturated with hexane, the-mixture filtered,

CH- COOH melting at 9496.

The starting material is prepared as follows:

To the solution of 52 g ethyl 4'-nitrophenylacetate in 350 mldimethylformamide-toluene (l :l 9.5 g of 50% sodium hydride in mineraloil are added portionwise while stirring and cooling. After 1 /2 hoursstirring at room temperature, 26 g methyl iodide are added dropwise andthe mixture is stirred overnight at room temperature. The mixture iscarefully combined with water, extracted with diethyl ether, the extractdried, filtered and evaporated. The residue is taken up in 100 mlethanol, the solution seeded with a few crystals starting material andallowed to stand in the cold. The precipitate formed is filtered off andthe filtrate evaporated, to yield the ethyla-(4-nitrophenyl)-propionate.

50 g thereof are hydrogenated in 200 ml 95% aqueous ethanol over 0.4 gpalladium on charcoal until the hydrogen uptake ceases. The mixture isfiltered and the filtrate evaporated, to yield the ethyla-(4-aminophenyl)-propionate; (its hydrochloride melts at l37l40). 25 gthereof are combined with ml acetic acid anhydride while stirring andcooling and the mixture is allowed to stand for one hour at roomtemperature. It is evaporated in vacuo and the residue recrystallizedfrom diethyl ether, to yield the ethyl a-(4-acetylaminophenyl)-propionate melting at 8890.

Through the solution of 25 g thereofin 100 ml acetic acid, chlorine isbubbled while stirring and cooling and the course of chlorination isfollowed by a thin layer ehromotography on silica gel in hexane-diethylether (1:4). After the consumption of starting material, the mixture isevaporated in vacuo, the residue taken up in 150 ml ethanol and hydrogenchloride is bubbled through the solution for 45 minutes. After refluxingfor 15 hours, it is evaporated and the residue recrystallized fromcthanoldiethyl ether, to yield the ethyl oz-(3-chloro-4-aminophenyl)-propionate hydrochloride, melting at l64-168.

EXAMPLE'4 To the solution of 25.1 gd,l-a-(3-chloro-4-pyrrolinophenyl)-propionic acid (Example 3) in 450 mldiethyl ether, 17.1 g d-a-( l-naphthyl)-ethylamine are added whilestirring and the mixture is evaporated in vacuo. The residue isrecrystallized 7 times from ethanoldiethyl ether, to yield thecorresponding salt melting at 133-135. 5 g thereof are dissolved in theminimum amount of 5% aqueous sodium hydroxide, the solution washed withdiethyl ether, its pH adjusted to 5.5 with hydrochloric acid andextracted with diethyl ether. The extract is dried, filtered andevaporated, to yield the da-(3-chl0ro-4-pyrrolinophenyl)-propionic acidhaving [01],, 34.8(ethanol).

EXAMPLE 5 The mixture of g ethyl 4-aminophenylacetate, 16.4 ga,a'-dibromo-o-xylene, 17.8 g sodium carbonate and 250 mldimethylformamide is refluxed for 6 hours while stirring. After cooling,it is diluted with water, extracted with diethyl ether, the extractwashed with water. dried. filtered, evaporated and the residuerecrystallized from diethyl ether, to yield the ethyl4-isoindolinophenylacetate of the formula melting at l l8l20.

EXAMPLE 6 The commercial 1,4-dibromo-2-butene, containing mainly thetrans epimer and being used in Examples 1 and 3, may be replaced by purecis-1,4-dichloro-2- butene. The mixture of 11.3 g thereof, 15.7 g ethyla-(4-aminophenyl)-propionate, 100 ml dimethylformamide and 10.6 g sodiumcarbonate is refluxed for 5 hours while stirring and allowed to standovernight at room temperature. It is filtered, the filtrate evaporatedin vacuo, the residue taken up in 260 ml 25% aqueous sodium hydroxideand the mixture refluxed for 8 hours. It is cooled, diluted with water,washed with diethyl ether and the pH adjusted to about 5 withhydrochloric acid. The mixture is extracted with diethyl ether, theextract dried. evaporated and the residue recrystallized from ethanol,to yield the a-(4-pyrrolino-phenyl)- propionic acid melting at ll7"-l9);it is identical with that obtained according to Example 2.

EXAMPLE? The mixture of 13.2 g ethyla-(3-chloro-4-aminophenyl)-propionate hydrochloride, 7.4 g phthalicanhydride, 10.1 g triethylamine and 200 ml toluene is refluxed for 6hours and evaporated in vacuo. The residue is taken up in water. themixture extracted wth diethyl ether, the extract dried, filtered.evaporated and the residue recrystallized from diethyl ether, to yieldthe ethyl a-[3-chloro-4-( l,3-dioxo-isoindolinolphenyl]-propionate ofthe formula melting at 5658.

The starting material is prepared as follows:

To the solution of 10 g ethyl 4-nitrophenylacetate in 400 mldimethylformamide-toluene (1:1), 2.5 g 50% sodium hydride are addedportionwise during 15 minutes while stirring and cooling with ice, afterwhich the solution of 9.6 g cyclopropylmethyl bromide in 50 ml tolueneis added dropwise and the mixture stirred overnight at room temperature.it is diluted with 200 ml water, extracted with diethyl ether, theextract dried, evaporated, the residue distilled and the fractionboiling at 132138/0.25 mm Hg collected. to yield the ethyla-(4-nitrophenyl)-B-cyclopropylpropionate.

The solution of 9 g thereof in ml ethanol is hydrogenated over 0.5 g 10%palladium on charcoal until the theoretical amount of hydrogen has beenabsorbed. The mixture is filtered, the filtrate evaporated in vacuo, theresidue taken up in diethyl ether, the solution gassed with hydrogenchloride, the precipitate formed filtered off and recrystallized fromethyl acetate, to yield the ethyla-(4-aminophenyl)-B-cyclopropylpropionate hydrochloride melting at 162.

EXAMPLE 9 ethyl a-(4-pyrrolinophenyll-isobutyrate ofthe formula I I l IIt re-G- a-c000 The starting material is 'preparedaccording time methoddescribed in Example 3,-but using 30.5 g methyl iodide instead of 26 g.By this variation, amixture of ethyl a-(4-aminophenyl)-propionateand-isobutyrate is obtained. The mixture of 4 g thereof (containingabout 20% of thelatter), Ll g potassium hydroxide, 250 ml ethanol and mlwater is refluxed for 1 /2 hours, cooled, diluted with water andextracted with diethyl ether. The extract is dried, evaporated, theresidue distilled and the fraction boiling at 3083l0/760 mm Hgcollected, to yield the ethyl a-(4-aminophenyl)-isobutyrate.

EXAMPLE The mixture of 4.6 g ethyl 4-isoindolinophenylacetate (Example5) and 80 ml 25% aqueous sodium hydroxide is refluxed for 3 hours,cooled and diluted with water. The mixture-is acidified withhydrochloric acid, the precipitate formed filtered off andrecrystallized from ethyl acetate, to yield the4-isoindolinophenylacetic acid melting at 237-239.

EXAMPLE 11 The mixture of 3 g ethylq-(4-pyrrolinophenyl):B-cyclopropylpropionate (Example 8) and ml 25% aqueous sodium hydroxide isrefluxed for 3 hours, cooled and diluted with water. It is acidifiedwith hydrochloric acid, the precipitate formed filtered off andrecrystallized from diethyl ether, to yield the a-(4-pyrrolinophcnyl)-,B-cyclo,propylpropionic acid melting at l35l37.

EXAMPLE l2 The mixture of 10 g ethyl 'a-(4-aminophenyl)- propionatehydrochloride, g a,a'-dibromo-'o-xylene, 16.5 gsodium carbonate and250ml dimethylformamide is refluxed for 5 hours while stirring. Aftercooling, it is filtered, the filtrate concentrated in vacuo, theconcentrate diluted with water, extracted with diethyl ether, theextract washed with water, dried, filtered and concentrated in vacuo.The precipitate formed is filtered off and recrystallized from ethanol.It is taken up in the minimum amount of benzene, the solution poured ona small column with silica gel and eluated with benzene. The firsteluate is evaporated and the residue recrystallized from ethanol, toyield the ethyl a-(4-isoindolinophenyl)-propionate of the formulamelting at l l ll 13.

The mixture of 1.8 g thereof, 5 ml 50% aqueous sodium hydroxide, l5mlwater and 100 ml ethanol is refluxed for 1% hour and concentrated invacuo. The

,concentrate is diluted with water, the suspension obmelting at '8991.

22,3 7 i-.-j-i BX mew The mixture of 5 g ethyl'4 aminophenylacetate, 4,9

t g homophthalic anhydride, 100 ml toluene and'0.5. ml

triethylamine is refluxed overnight at the watertrap and evaporated invacuo. The residue is recrystallized from ethanol with the use ofcharcoal, to yield the ethyl 4-( 1,3-dioxo-l ,2,3,4-tetrahydi'oisoquinolino )-phenyl acetate of the formula EX'AMPLEJVM ITo the solution of' 0.5g ethyl o -(4 -isoin'dolinophenyl)-propionate in50 ml glacial acetic acid, 6 ml of I glacial acetic acid saturated withchlorine are added dropwise while stirring and the mixture is evaporatedin vacuo. The residue is taken up in aqueous sodium bi-'carbonate,the-mixture extracted with diethyl ether, the extract dried,filtered and evaporated. The residue is chromatographed on silica gelusing benzene-hexane (1:1) as the mobile phase, to yield as the majorproduct the ethyl. a-(3-chloro-4-isoindolinophenyl)+propionate Qfthfqtmula 1 t moving 30 mm (as compared to26 mm for the starting material)and a minor portion of the. ethyl a-(3,5dichloro-4-isoindolinophenyl)-propionate of the formula moving 39.5 mmin said system.

EXAMPLE 15 the aqueous layer extracted with methylene chloride. I

The combined organic solutions are dried, filtered and concentrated, toyield the a-(3-chloro-4-pyrrolinophenylt-propionic a Nrwsiaet thef ma e.

melting at 140-142.

EXAMPLE 16 To the mixture of 9.8 g maleic anhydride and 150 ml diethylether, the solution of 17.9 'g ethyl 4- aminophenylacetate in 150 mldiethyl ether is added dropwise while stirring at room temperature.After 1 /2 hour, the mixture is cooled, filtered and the residuerecrystallized from acetone, to yield the ethyl-4-(B-carboxyacryloylamino)-phenyl-acetate melting at 152-154; (theanalogously prepared a-[4-(B- carboxyacryloylamino)-phenyll-propionatemelts at l28130 after recrystallization from diethyl ether, and its3-chloro derivative melts at 86-88 after recrystallization fromhexane-diethyl ether).

The mixture of 14 g thereof, 50 ml acetic anhydride and 4 g sodiumacetate is heated on a steam bath for 45 minutes and poured onto icewater. It is filtered and the residue recrystallized from cyclohexane,to yield the ethyl 4-(2,5-dioxopyrrolino)-phenyl-acetate of the formulamelting at 77-79. The analogously prepared propionate melts at 87-89(hexane).

EXAMPLE 17 The mixture of 24 g ethyl a-(4-amino-3-chlorophenyl)-butyrate, 21 g sodium carbonate, 25 gcis-l,4-dichloro-2-butene and 250 ml dimethylformamide is refluxed for12 hours. After cooling, it is diluted with diethyl ether, filtered andthe filtrate evaporated. 1 1 g of the residue are taken up in 100 mlethanol and 20 ml 25% aqueous sodium hydroxide, the mixture refluxed for6 hours and evaporated in vacuo. The residue is taken up in water, thesolution washed with diethyl ether, the pH adjusted to 5.5 withhydrochloric acid and extracted with diethyl ether. The extract isdried, evaporated and the residue recrystallized from hexane, to yieldthe a-(3-chloro-4-pyrrolinophenyl)- butyric acid of the formula l... Zae melting at l03-105.

The starting material is prepared as follows: To the mixture of 104 gethyl 4-nitroph'enyl-acetate, 350 ml dimethylformamide and 350 mltoluene, 19 g 50% sodium hydride in mineral oil are added during hour at10 while stirring. After 1 /2 hours, 78 g ethyl iodide are added during1 hour while stirring. After 1 /2 hours,

at. and room temperature. After the hydrogen uptake has ceased, themixture is filtered, the filtrate evaporated, the residue taken up in 2Nhydrochloric acid. the solution washed with diethyl ether, made basicwith aqueous sodium hydroxide, extracted with diethyl ether and theextract evaporated, to yield the ethyl a-(4-aminophenyl)-butyrate.

The mixture of 35 g. thereof and 100 ml acetic anhydride is stirred for1 hour at the steam bath and evaporated, to yield the ethyl-a-(4-acetylaminophenyl)- butyrate.

Through the solution of 35 g thereof in 200 ml acetic acid, chlorine isbubbled at 15-20 while stirring and the course of the reaction followedby thin layer chromatography on silica gel in hexane-diethyl ether 1:4). After the consumption of starting material, the mixture isevaporated, to yield the ethyl a-(4-acetylamino-3-chlorophenyl)-butyrate hydrochloride.

Through the solution of 36 g thereof in 200 ml ethanol, hydrogenchloride is bubbled through while stirring for 45 minutes. The mixtureis refluxed for 20 hours, allowed to stand for 24 hours at roomtemperture and evaporated. The residue is taken up in water, thesolution made basic with aqueous sodium hydroxide, extracted withdiethyl ether, the extract dried, evaporated, the residue distilled andthe fraction boiling at 130-132/0.4 mm Hg collected, to yield the ethyla-(4-amino-3-chlorophenyl)-butyrate.

EXAMPLE 18 The mixture of 0.63 g methyl a-cyclopropyl-(4-amino-3-chlorophenyl)-acetate hydrochloride, 0.55 gcis-l,4-dichloro-2-butane, 0.7 g sodium carbonate and 50 mldimethylformamide is refluxed under nitrogen for 10 hours and stirred atroom temperature for 2 days. It is filtered, the filtrate evaporated,the residue taken up in water, the mixture extracted with diethyl etherand the extract evaporated in vacuo. The residue is taken up in 35 mlethanol, 0.5 ml water and 0.28 g potassium hydroxide are added, themixture refluxed for 2 hours and evaporated in vacuo. The residue istaken up in water, the solution washed with diethyl ether, the pHadjusted to 4-4.5 with hydrochloric acid and the mixture extracted withethyl acetate. The extract is dried, evaporated and the residuerecrystallized from diethyl ether, to yield the oz-cyclopropyl-(3- C hl0t'Q- 4:Byrro li n op henyl) -acetic acid of the formula melting at152156.

The starting material is prepared as follows: To the solution of 200 ga-cyclopropyl-phenylacetic acid in 1.2 liters trifluoroacetic acid, themixture of 73 ml aqueous nitric acid and 9.1 ml 96% aqueous sulfuricacid is added dropwise while stirring and cooling to about 3. After 1 /2hours, the temperature is allowed to rise to room temperature and themixture stirred for a total of 3 additional hours. It is dropped onto3.2 kg ice and 300 ml water while stirring, filtered, the residue washedwith 6 liters water and dried, to yield an about 2:1 mixture ofa-cyclopropyl-(4- and 2-nitrophenyl)- acetic acid.

The mixture of 50 g thereof, 5 g 10% palladium on charcoal and 550ml aqueou s ethanol is hydrogenated at atmospheric pressure until 15.9liters hydrogen have been consumed. It is filtered, the filtrateconcentrated, the precipitate formed in the cold separated andrecrystallized once more from ethanol, to yield the purea-cyclopropyl-(4-aminophenyl)-acetic acid.

To the mixture of g thereof and 75 ml methanol, 75 ml saturatedmethanolic hydrogen chloride are added while stirring and cooling in anice bath. After /2 hour, the mixture is heated to 38 for 1 hour andstirred at room temperature overnight. It is cooled, combined with 100ml water and 105 ml 20% aqueous sodium hydroxide are added while coolingand stirring. The precipitate formed in filtered off, washed with waterand dried, to yield the methyl oz-cyclopropyl-(4- aminophenyU-acetate,melting at 68-69.

The mixture of 12 g thereof and 100 ml acetic anhydride is stirred for 1hour at the steam bath and evaporated. The residue is taken up inbenzene and the mixture again evaporated, to yield the methyla-cyclopropyl-(4-acetylaminophenyl)-acetate melting at 159162.

The the solution of 1.6 thereof in 50 ml acetic acid, 30 ml of asaturated solution of chlorine in acetic acid is added dropwise whilestirring and the mixture evaporated in vacuo. The residue is taken up 2times in benzene and the mixture evaporated, to yield the methyla-cyclopropyl-(4-acetylamino-3-chlorophenyl)- acetate.

Through the solution of 1.6 g thereofin 200 ml methanol, hydrogenchloride is bubbled for 15 minutes and the mixture refluxed for 21hours. It is evaporated in vacuo, the residue taken up in 6Nhydrochloric acid, the mixture washed with diethyl ether, made basicwith aqueous sodium hydroxide and extracted with diethyl ether. Theextract is dried, evaporated, the residue taken up in diethyl ether, thesolution acidified with ethereal hydrogen chloride and the precipitateformed filtered off, to yield the methyl a-cyclopropyl-(4-amino-3-chlorophenyl)-acetate hydrochloride melting at l64-l69.

EXAMPLE 19 N j CH- COONa 1 c1 CH3 melting at 207209.

EXAMPLE 20 3 g of the lithium salt of the ethyl 4-(4-oxopiperidino)-phenylacetate-N-p-toluenesulfonylhydrazone is slowlyheated first to about 3040 and the 0.3 mm Hg to effect final drying, andthen to 80-l35 for 45 minutes. The residue is taken up in the minimumamount of ethanol, the solution poured on a small column with silica geland eluted with benzene. The first 26 eluate obtained is evaporated, toyield the ethyl 4-piperideinowphenylacetate of the formula ;N -CH2 (100011 showing in the IR. spectrum bands at 5.86 and 6.08 t.

The starting material is prepared as follows: The mixture of 89.6 gethyl 4-aminophenylacetate, 400 g ethyl acrylate and ml acetic acid isrefluxed for 19 hours and concentrated in vacuo. The concentrate ispoured onto 500 ml ice water, the mixture made basic with aqueous sodiumhydroxide and extracted with diethyl ether. The extract is dried,filtered, evaporated, the residue distilled and the fraction boiling at2112l3/0.6 mm Hg collected, to yield the ethyl4-(biscarbethoxyethylamino)-phenyl-acetate.

To the solution of 38 g thereof in 100 ml ethanol, that obtained from3.4 g sodium and 100 ml ethanol is added dropwise and the mixturerefluxed for 7 hours. It is evaporated in vacuo, the residue taken up inwater, the mixture extracted with diethyl ether, the extract dried,filtered and evaporated, to yield the ethyl 4-(3-carbethoxy-4-oxopiperidino)-phenylacetate.

The mixture of 30.5 g thereof and 300 ml 50% sodium hydroxide is heatedat the steam cone for 12 hours. It is cooled, acidified withconcentrated hydrochloric acid and the mixture heated for 6 hours. It isevaporated in vacuo, the residue taken up in ethanolic hydrogenchloride, the mixture evaporated again, the residue taken up in water,the mixture made basic with aqueous sodium hydroxide, extracted withdiethyl ether, the extract dried and evaporated, to yield the ethyl4-(4-oxopiperidino)-phenylacetate.

The mixture of 5.2 g thereof, 2.1 g 4-p-toluenesulfonylhydrazide, 3 mlglacial acetic acid and 5.0 ml ethanol is refluxed for 30 minutes. lt iscooled, the precipitate formed filtered off and taken up in the minimumamount oftetrahydrofuran. To the solution, 13 ml 1.6N n-butyl lithiumare added dropwise while still under nitrogen at 0-5. After 30 minutes,the mixture is evaporated at a temperature below 35, to yield thelithium salt of the ethyl 4-(4-oxopiperidino)-phenylacetate-N-p-toluenesulfonylhydrazone.

EXAMPLE 21 Preparation of 10,000 tablets each containing 25.0 mg of theactive ingredient:

Formula: oz-( 3-chloro-4-pyrrolinophenyl)-propionic acid 250.00 gLactose 1,956.00 g Corn starch 90.00 g Polyethylene glycol 6,000 90.00 gTalcum powder Magnesium stearate 24.00 g Purified water q.s.

27 which are granulated, if necessary, with an additional amount ofwater. The granulate is dried overnight at 35, broken on a screen with1.2 mm openings and compressed into tablets using concave punches with7.1 mm diameter, uppers bisected.

In the analogous manner, tablets can be prepared containing the sameamount of another preferred drug substance of Formula II, e.g. theoz-(4-pyrrolinophenyl)-propionic acid.

EXAMPLE 22 Preparation of 1,000 tablets, each containing 25 mg of theactive ingredient:

All the powders are passed through a screen with openings of 0.6 mm.Then the carrier materials are blended and the drug substance is addedgradually. After thorough mixing, the powder is compressed into tabletsusing concave punches with 4.8 mm diameter. Instead ofthe above drugsubstance. the corresponding sodium salt described in Example 19 can beused.

EXAMPLE 23 The starting material used in Example 3 can also be preparedas follows: 4.8 g 50% sodium hydride in mineral oil are added to 100 mlhexamethylphosphoramide while stirring under nitrogen. Hereupon 17.1 gdiethyl oz-methylmalonate are added and the mixture slowly heated to100. The solution of 19.2 g 2,4-dichloronitrobenzene in 20 mlhexamethylphosphoramide is added dropwise during V2 hour and thetemperature kept at 100 for 7 hours. After cooling, the mixture isdiluted with water, concentrated in vacuo, the residue taken up in waterand extracted with benzene. The extract is washed with water, dried,filtered, evaporated, the residue distilled and the fraction boiling at147 /0.25 mm Hg collected, to yield the diethyla-methyl-a-(3-chloro-4-nitrophenyl)-malonate. (The analogously prepareddiethyl a-ethyl-a-(3-chloro-4- nitro-phenyl)-malonate boils at l70l4l74/l mm Through the solution of 4 g thereof in 50 ml anhydrous ethanol,hydrogen chloride is bubbled for 5 minutes. Hereupon 0.5 g palladium oncharcoal are added and the mixture hydrogenated for 10 minutes at aninitial pressure of 3 at. It is filtered and the filtrate evaporated invacuo. The residue is taken up in 5% aqueous sodium hydroxide, themixture extracted with diethyl ether, the extract dried, filtered andevaporated, to yield the diethyl a-methyl-a-(3-chloro-4-aminophenyl)-malonate, showing in the LR. spectrum bands at 1,720, 3,370and 3,460 cm".

The mixture of g thereof and ml 50% aqueous sodium hydroxide is refluxedovernight, cooled, diluted with water and washed with diethyl ether. Itis acidified with concentrated hydrochloric acid, the mixture againrefluxed overnight and evaporated in vacuo. The residue is taken up inanhydrous ethanolic hydrogen chloride, the mixture refluxed for 6 hours,evaporated and the residue recrystallized from ethanol-diethyl ether, toyield the ethyl a-(3-chloro-4-aminophenyl)-propionate hydrochloridemelting at l64l68.

EXAMPLE 24 The combined mother liquors obtained in the preparation ofthe d-a-( l-naphthyl)-ethylammonium d-a-(3-chloro-4-pyrrolinophenyl)-propionate, melting at l33-l 35 and having [a]9.6 according to Example 4, are evaporated in vacuo and the residuetaken up in water. The pH of the solution is adjusted to 5.5 withhydrochloric acid and extracted with diethyl ether. The extract isdried, filtered and evaporated. 8.4 g thereof are taken up in 20 mldiethyl ether and 5.7 g 1-a-(l-napthyl)-ethylamine in 35 ml diethylether are added. The precipitate formed in recrystallized 5 times fromethanol-diethyl ether, to yield the corresponding salt melting atl32-l33, [011 -9.l. 10 g thereof are dissolved in the minimum amount of5% aqueous sodium hydroxide, the solution washed with diethyl ether, itspH adjusted to 5.5 with hydrochloric acid and extracted with diethylether. The extract is dried, filtered and evaporated, to yield thel-a-(3-chloro-4- pyrrolinophenyl)-propionic acid having [cr],, 38.4(ethanol, a more purified sample of its antipode has [or],, +39.6).

I g thereof is taken up in the minimum amount of water and the solutionadjusted to pH 8 with aqueous sodium hydroxide. The solution isevaporated in vacuo, the residue taken up in ethanol, filtered, thefiltrate concentrated and the concentrate diluted with diethyl ether, toyield the sodium l-a-(3-chloro-4-pyrrolinophenyl)-propionate, melting at205-208, [041 =+l7.4. The analogously prepared sodium salt of thedextrorotatory acid of Example 4 melts at 2l2-2l4, [(1510 l7.4.

EXAMPLE 25 'dioxopyrrolino)-phenyl]-propionate of the formula showing inthe N.M.R. spectrum peaks at 1.2 (triplet),

1.5 (doublet), 3.7 (quartet) and 6.9 ppm (singlet).

The starting material is prepared as follows: To the solution of 7.4 gethyl a-(4-amino-3-chlorophenyl) P 9 a 50 1 earest; a l iasabx s 29 in25 ml diethyl ether are added, the mixture slowly concentrated to 30 mland diluted with hexane. After standing overnight at room temperature,the precipitate formed is filtered off, to yield the ethyl a-[3-chloro-4-(B-cis-carboxy-acryloylamino)-phenyl]- propionate, melting at8688.

EXAMPLE 26 Preparation of 10,000 capsules each containing 25 mg of theactive ingredient:

Formula: a-( 3-chloro-4-pyrrolinophenyl) propionic acid 250 gMicrocrystalline celluose 1.080 g Hardened vegetable oil fractionmelting at 6580 20 g Procedure All the powders are passed througha'screen with openings of 0.6 mm. Then the drug substance is placed in asuitable mixer and mixed first with the oil fraction and then with thecellulose until homogeneous. 135 mg of the mixture are filled into 0.3ml hard gelatine capsules, using a capsule filling machine.

EXAMPLE 27 EXAMPLE 28 The mixture of 22.8 g ethyla-(4-amino-3-chlorophenyl)-propionate, l9.8 g ethyl2-chloromethylbenzoate, 15 ml triethylamine and 300 ml ethanol isallowed to stand overnight and slowly evaporated. The residue is takenup in water, the mixture extracted with diethyl ether, the extractwashed with 5% hydrochloric acid and water, dried, filtered andevaporated. The residue is taken up in 250 ml ethanol, 100 ml aqueouspotassium carbonate are added and the mixture slowly evaporated invacuo. The residue is taken up in water, the solution filtered, the pHof the filtrate adjusted to 4 with hydrochloric acid and extracted withethyl acetate. The extract is washed with water, dried and concentrated,to yield the a-[ 3-chloro-4-( loxoisoindolino)-phenyl]-propionic acid ofthe formula G?- CH 0 C1 7 The ethyl ester thereof can also be preparedby bubbling air through a concentrated solution of the compounds ofExamples 14 or 27 in dimethylformamide for 2 hours at 60 while stirring.The mixture is evaporated in vacuo, the residue distilled and thefraction boiling at 200-2l0/0.4 mm Hg collected.

EXAMPLE 29 According to the methods described in the previous examples,the following compounds are prepared from equivalent amounts of thecorresponding starting materials:

a. a-[3-chloro-4-(2-oxopyrrolino)-phenyl]-propionic acid;

b. a-[3-chloro-4-(2-methyl-5-oxopyrrolino)-phenyl]- propionic acid;

c. a-[4-(3,4-dichloro-2,S-dioxopyrrolino)-phenyl]- propionic acid;

d. a-[3-chloro-4-(5-chloro-l-oxoisoindolino)-phenyl]- propionic acid;

e. a-[3-chloro-4-(6-pyrrolo[3,4-b]pyridyl)-phenyl]- propionic acid;

f. a-[3-chloro-4-(5- or 7-oxo-6-pyrrolo[3,4-b]pyridyl)-phenyl]-propionic acid; I v

g. a-[3-chloro-4-(5,7-dioxo-6-pyrrolo[3,4-b]pyridyl)- phenyl]-propionicacid, the methyl or ethyl esters thereof, or the sodium or potassiumsalts thereof.

EXAMPLE 30 Preparation of a cream containing 2% of the activeingredient.

ethyl a-[3-chl0r0-4-(2,5-dioxopyrrolino)-phenyll-propionate WhitePetrolatum Spermaceti Stearyl Alcohol Cetyl Alcohol Stearic AcidGlycerine Sodium Lauryl Sulfate Purified Water Procedure The mixture ofthe petrolatum, spermaceti, stearyl and cetyl alcohols and stearic acidis molten and the liquid strained into a mixing kettle heated to aboutThe drug substance, admixed with the sodium lauryl sulfate, is suspendedin the glycerine-water solution, which is heated to 72 and slowly addedto the fats while mixing vigerously until a homogenous cream has formed.

We claim:

1. An a-(cyclic tert. aminophenyl)-aliphatic acid of the formula inwhich R is hydrogen or lower alkyl, R is hydrogen, lower alkyl, loweralkenyl, 3 to 7 ring-membered cycloalkyl, cycloalkenyl, cycloalkyl-loweralkyl or cycloalkenyl-lower alkyl, Ph is unsubstituted phenylene orphenylene substituted by one or two halogen atoms or one member selectedfrom the group consisting of lower alkyl, lower alkoxy, trifluoromethyl,nitro, amino or di-lower alkylamino, and

is monocyclic to 7 ring membered 2- or 3- alkenyleneimino, or a loweralkyl ester, the amide, a monoor di-lower alkylamide, the N-oxide, or atherapeutically acceptable alkali metal or alkaline earth metal salt oracid addition salt thereof in which compounds lower defines such groupswith up to 4 carbon atoms.

2. A compound as claimed in claim 1, in which formula R Ph and have themeaning given in claim 1, and R is 3 or 4 ringmembered cycloalkyl,cycloalkenyl, cycloalkyl-lower alkyl or cycloalkenyl-lower alkyl,wherein lower defines such groups with up to 4 carbon atoms, or thefunctional derivatives thereof listed in claim 1.

3. A compound as claimed in claim 1, in which formula R is hydrogen, Ris hydrogen or lower alkyl, Ph is 1.3- or l,4-phenylene, (loweralkyl)-l,3- or 1,4- phenylene, (lower-alkoxy)- 1,3- or 1,4-phenylene,monoor di(halogeno)-1,3-or 1,4-phenylene, (trifluoromethyl)-l,3- or1,4-phenylene, (nitro)-l,3- or 1,4-phenylene, (amino-1,3- or1,4-phenylene, or (dilower alkylamino)- 1,3 or l,4-phenylene, and thegroup is monocyclic 5 to 7 ring-membered 2-or 3-alkenyleneimino, or alower alkyl ester, the amide, a monoor dilower alkylamide, the N-oxide,an alkali metal or alkaline earth metal salt or a therapeutically usefulacid addition salt thereof in which compounds lower defines such groupswith up to 4 carbon atoms.

4. A compound as claimed in claim 1, in which formula R Ph and Pa \J ahave the meaning given in claim 4, and R is 3 or 4 ringmemberedcycloalkyl or cycloalkyl-lower alkyl, or the functional derivativesthereof listed in claim 4.

5. A compound as claimed in claim 3 and having the formula Am-Q-(JH-CoOH formula Am-|CHCOOH in which R is 3 or 4 ring-membered cycloalkylor cycloalkyl-methyl, R is hyrdogen, alkyl or alkoxy with up to 4 carbonatoms, fluoro, chloro, trifluoromethyl, nitro or amino, and Am is3-pyrrolino, 3-piperideino or 1,6-hex-3-enyleneimino, or the methyl,ethyl, nor ipropyl or butyl ester, the N-oxide, sodium or potassium saltor a therapeutically useful acid addition salt thereof.

7. A compound as claimed in claim 5, in which formula R is hydrogen ormethyl, ethyl nor i-propyl, R4is hydrogen, fluoro, chloro, ortrifluoromethyl and Am is 3-pyrrolino or 3-piperideino, or the methyl orethyl ester, the N-oxide, sodium or potassium salt or a therapeuticallyuseful acid addition salt thereof.

8. A compound as claimed in claim 7, in which formula R is cyclopropy]or cyclopropylmethyl, R is hydrogen, fluoro, chloro or trifluoromethyland Am is 3- pyrrolino or 3-piperideino, or the methyl or ethyl ester,the N-oxide, sodium or potassium salt or a therapeutically useful acidaddition salt thereof.

9. A compound as claimed in claim 8 and being thea-(3-chloro-4-pyrrolinophenyl)-propionic acid.

1. AN A(CYCLIC TERT. AMINOPHENYL)-ALIPHATIC ACID OF THE FORMULA
 2. Acompound as claimed in claim 1, in which formula R1, Ph and
 3. Acompound as claimed in claim 1, in which formula R1 is hydrogen, R2 ishydrogen or lower alkyl, Ph is 1,3- or 1,4-phenylene, (lower alkyl)-1,3-or 1,4-phenylene, (lower-alkoxy)-1,3- or 1,4-phenylene, mono- ordi(halogeno)-1,3-or 1,4-phenylene, (trifluoromethyl)-1,3- or1,4-phenylene, (nitro)-1,3-or 1,4-phenylene, (amino-1,3- or1,4-phenylene, or (di-lower alkylamino)- 1,3- or 1,4-phenylene, and thegroup
 4. A compound as claimed in claim 1, in which formula R1, Ph and5. A compound as claimed in claim 3 and having the formula
 6. A compoundas claimed in claim 4 and having the formula
 7. A compound as claimed inclaim 5, in which formula R3 is hydrogen or methyl, ethyl n- ori-propyl, R4is hydrogen, fluoro, chloro, or trifluoromethyl and Am is3-pyrrolino or 3-piperideino, or the methyl or ethyl ester, the N-oxide,sodium or potassium salt or a therapeutically useful acid addition saltthereof.
 8. A compound as claimed in claim 7, in which formula R3 iscyclopropyl or cyclopropylmethyl, R4 is hydrogen, fluoro, chloro ortrifluoromethyl and Am is 3-pyrrolino or 3-piperideino, or the methyl orethyl ester, the N-oxide, sodium or potassium salt or a therapeuticallyuseful acid addition salt thereof.
 9. A compound as claimed in claim 8and being the Alpha -(3-chloro-4-pyrrolinophenyl)-propionic acid.